The sigma-1 receptor is an intracellular chaperone protein that resides specifically at the endoplasmic reticulum (ER)-mitochondrion interface, referred to as the mitochondrion-associated ER membrane (MAM). It is expressed in the central nervous system (CNS) in microglia, lymphocytes, neurons, and oligodendrocytes and is known to be implicated in the regulation of numerous neurotransmitters.
In the central nervous system (CNS), Sig-1Rs play a part in complex biological processes, which include cocaine or methamphetamine addiction, learning and memory, pain and depression. Some reports using the molecular biological silencing approach have implicated these receptors in neurodegenerative disorders such as Alzheimer's disease, stroke, and neural degeneration due to HIV infection.
Sig-1Rs are thus potential therapeutic targets in multiple CNS diseases and a variety of Sig-1R agonists and antagonists have been described.
Anavex 2-73 (1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine hydrochloride) exhibits high affinity and selectivity to sigma-1 receptors and synergistic action with muscarinic and cholinergic receptors. Additional activities have been demonstrated on N-methyl-D-aspartate (NMDA) receptors. During in vitro and in vivo preclinical studies in mice, Anavex 2-73 demonstrated neuroprotective and anti-amnesic properties. Anavex 2-73 has been shown to provide protection from oxidative stress, which damages and destroys neurons and is believed to be a primary cause of Alzheimer's disease. Anavex 2-73 is currently under Phase I clinical trials.
Anavex 1-41 (1-(5,5-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine hydrochloride) presents a mixed pharmacological activity involving the modulation of both sigma-1 and muscarinic components showing prominent anti-amnesic, anti-depressant at low sigma-1 agonistic doses. In addition, it presents mixed pharmacological activity involving the modulation of sodium and chloride channels.
Donepezil ((RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one) is an acetylcholine esterase inhibitor having non-selective sigma-1 agonistic activity. Donepezil is also an agonist of muscarinic and nicotinic receptors, and is a marketed drug used in the palliative treatment of Alzheimer's disease.
Other molecules having Sig-1R affinity are known but they either lack subtype selectivity over Sig-2R or they have high affinity for other receptors sites as do Anavex 1-41 and 2-73, and donepezil.
Drugs having poor selectivity (i.e. modulating the activity of multiple receptors) are more susceptible to inducing deleterious side effects, in particular to patients who are already under other medications.
There is therefore still a need for new selective modulators, especially agonists, of sigma-1 receptor activity of therapeutic value for the treatment and/or prevention of sigma-1 receptor related diseases, especially neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis.